Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate plasma glucose levels. Two major forms of diabetes are recognized. Type I diabetes (T1D), or insulin-dependent diabetes mellitus, is the result of an absolute deficiency of insulin. Type II diabetes (T2D), or non-insulin dependent diabetes mellitus, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of T2D with medication is essential; otherwise it can progress into β-cell failure and insulin dependence.
Glucagon is a twenty-nine amino acid peptide which is secreted from the acells of the pancreas into the hepatic portal vein thereby exposing the liver to higher levels of this hormone than non-hepatic tissues. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma non-esterified fatty acid levels and somatostatin whereas glucagon secretion is increased in response to hypoglycemia and elevated plasma amino acid levels. Glucagon, through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis. In T2D individuals, basal glucagon levels are high and inadequately suppressed by hyperglycemia and hyperinsulinemia.
The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors. The glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP.
Genetic disruption of glucagon receptor expression in mice (Gcgr−/−) lowers fasting and fed glucose levels and improves glycemic control. However, the Gcgr−/− mice develop hyperglucagonemia, pancreatic a cell hyperplasia, and pancreatic neuroendocrine tumors (Gelling, R. W. et al., 2003, “Lower plasma glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice” Proc. Natl. Acad. Sci. U.S.A. 100: 1438-1443; Yu, R. et al., 2011, “Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice” Plos ONE 6(8): e23397). Similarly, a human patient born with a homozygous inactivating GCGR mutation (P86S) develops pancreatic neuroendocrine tumors and exhibits hyperglucagonemia and pancreatic a cell hyperplasia (Yu, R. et al., 2008, “Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas” Pancreas 36: 428-431).
Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, T2D (Moller, D. E., 2011, “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414: 821-827): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease plasma glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.
From the information available in the art, and prior to the present invention, it remained unclear whether the introduction of anti-glucagon receptor antagonist antibody into the blood circulation to selectively antagonize glucagon receptor would be safe and effective to lower plasma glucose levels and prevent and/or treat diabetes, and, if so, what properties of an anti-glucagon receptor antibody are needed for such in vivo safety and effectiveness.